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Abstract:

A multilayered solid oral pharmaceutical formulation of trimetazidine or
a pharmaceutically acceptable salt or polymorph of trimetazidine wherein
one layer of said formulation provides controlled release, while the
other layer provides immediate release.

Claims:

1. A multilayered solid oral pharmaceutical formulation of trimetazidine
or a pharmaceutically acceptable salt or polymorph of trimetazidine,
comprising a first layer of said formulation providing controlled release
wherein a controlled-release providing agent is used in an outer granule
phase, while a second layer provides immediate release.

2. The pharmaceutical formulation according to claim 1, further
comprising at least one or more excipients.

3. The pharmaceutical formulation according to claim 1, comprising
preferably at least one intermediate layer between said first and second
layers.

4. The pharmaceutical formulation according to claim 1, said tablet
containing trimetazidine dihydrochloride wherein the amount by weight of
trimetazidine dihydrochloride in said immediate-release layer is not more
than 25% by weight of the total amount of trimetazidine dihydrochloride
present in the tablet.

5. The pharmaceutical formulation according to claim 1, said tablet
containing trimetazidine dihydrochloride wherein the amount by weight of
trimetazidine dihydrochloride in said immediate-release layer is not more
than 10% by weight of the total amount of trimetazidine dihydrochloride
present in the tablet.

15. The pharmaceutical formulation according to claim 11, wherein said
diluent is selected from at least one of calcium hydrogen phosphate
dihydrate and dicalcium hydrogen phosphate anhydrate.

16. The pharmaceutical formulation according to claim 11, wherein said
glidant comprises at least one or a mixture of colloidal silicone
dioxide, talc, aluminum silicate, and magnesium silicate.

17. The pharmaceutical formulation according to claim 11, wherein the
lubricant used comprises magnesium stearate.

18. A pharmaceutical formulation, consisting of: a. an immediate-release
layer having: a) trimetazidine dihydrochloride at 0.1 to 10% by weight;
b) dicalcium hydrogen phosphate anhydrate at 5 to 90% by weight; c)
colloidal silicone dioxide at 0.1 to 5% by weight; d) magnesium stearate
at 0.1 to 5% by weight; and e) red iron oxide at 0.01 to 5% by weight;
and b. a controlled-release layer having: a) trimetazidine
dihydrochloride at 2.5 to 50% by weight; b) polyethylene oxide at 2 to
90% by weight; c) polyvinylpyrrolidone at 0.1 to 20% by weight; d)
calcium hydrogen phosphate dihydrate at 5 to 90% by weight; e) colloidal
silicone dioxide at 0.1 to 5% by weight; and f) magnesium stearate at 0.1
to 5% by weight.

19. A method for preparing a pharmaceutical formulation according to
claim 1, said method comprising the steps of: a) sieving and then mixing
trimetazidine dihydrochloride, polyvinylpyrrolidone and calcium hydrogen
phosphate dihydrate in a high-shear mixer; b) granulating the mixture
from above with sufficient amount of water; c) sieving the wet granules
formed, then drying the same and sieving back the dried granules; d)
adding polyethylene oxide and colloidal silicone dioxide into the
granules obtained and mixing the latter; e) sieving magnesium stearate
and mixing it into the resultant mixture to obtain the controlled-release
phase; f) sieving and mixing together trimetazidine dihydrochloride,
dicalcium hydrogen phosphate anhydrate, colloidal dioxide and red iron
oxide; g) sieving magnesium stearate and mixing it into the resultant
mixture to obtain the immediate-release phase; and h) compacting the
controlled-release phase and immediate-release phase to provide a bilayer
tablet.

20. The pharmaceutical formulation according to claim 1 for preventing or
treating angina pectoris, chorioretinal vascular disorders, tinnitus,
vertigo, and meniere's syndrome in mammalians and particularly in humans.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is based upon Turkish Patent Application No.
TR201003511, filed May 5, 2010, under relevant sections of 35 USC
§119, the entire contents of this application being incorporated by
reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to formulations of trimetazidine or a
pharmaceutically acceptable salt of trimetazidine. The present invention
more particularly relates to a formulation of trimetazidine, providing
immediate release and controlled release concomitantly.

BACKGROUND OF THE INVENTION

[0003] Trimetazidine, with the chemical name
1-(2,3,4-trimethoxybenzyl)piperazine, has the following chemical
structure of Formula I.

##STR00001##

[0004] Trimetazidine is an anti-ischemic agent and used in the prophylaxis
and treatment of angina pectoris and vertigo. It has considerably high
solubility and is rapidly absorbed upon administration. Its half-life is
6 hours.

[0005] There are various patent applications available in relation to
trimetazidine. For example, EP0533579 discloses trimetazidine derivatives
and a process for obtaining the same.

[0006] EP0673649 discloses a pharmaceutical composition providing
prolonged release of trimetazidine or a pharmaceutically acceptable salt
thereof. Prolonged release of trimetazidine is controlled by means of a
reservoir system in this composition. In this reservoir system, a mixture
of a water-insoluble polymer and a plasticizer is in the form of a film
that coats tablets or minigranules containing trimetazidine or an
addition salt thereof, together with a pharmaceutically acceptable acid.
The plasticizing agent here is not hydrogenated oil.

[0007] EP1108424 discloses a matrix object for prolonged release of
trimetazidine or a pharmaceutically acceptable salt thereof, of which the
prolonged release is controlled by using a polymer derived from
cellulose, selected among hydroxypropyl methyl cellulose, hydroxyethyl
cellulose, hydroxymethyl cellulose, methyl cellulose, hydroxypropyl
cellulose.

[0008] EP1448173 discloses a process for preparing a "once a day" drug
containing 60 mg trimetazidine dihydrochloride and having an
pH-independent in vitro release, as well as a novel composition prepared
by this process. This composition is composed of uniformly-shaped and
sized microbeads.

[0009] Various formulations have been developed with trimetazidine.
Reviewed generally, it can be concluded that there are various
conventional tablets and controlled-release formulations of trimetazidine
molecule. The posology of such formulations is in the form of
administering 3 conventional products or 2 controlled-release products
per day. "Once a day" administration of doses gains high importance and
need with respect to patients. EP 1 448 173 discloses a
controlled-release tablet containing 60 mg trimetazidine dihydrochloride
and claims to treat patients, needing such treatment, by administering
one dose thereof daily. A certain period of time is required, however, to
the onset of the effect of said formulation. This is not desirable for
the patient. A quick onset of the treatment process directly affects
patient life quality.

[0010] Trimetazidine dihydrochloride is highly-soluble in water. It is
therefore quite difficult to develop a formulation of highly-soluble
trimetazidine dihydrochloride with release profiles of desired quality.
For instance, such release profiles may show fluctuations. On the other
hand, polymers providing proper release profiles impose problems, such as
sticking to punches and other equipment during production, due to their
viscosities.

[0011] Considering the aforesaid problems, it is obvious that a novelty is
needed in both providing production convenience in the art of "once a
day" dose formulations containing trimetazidine dihydrochloride, and
ensuring convenient release profiles for the same.

[0013] Accordingly, the main object of the present invention is to provide
a trimetazidine formulation administered orally once or twice per day.

[0014] Another object of the present invention is to reduce the treatment
onset time, while said formulation provides a 24-hour effect.

[0015] A further object of the present invention is to prevent the
production items from sticking to contact surfaces of machines and
equipment.

[0016] A solid oral pharmaceutical formulation comprising trimetazidine or
a pharmaceutically acceptable salt or polymorph of trimetazidine and
having multiple layers has been developed to carry out all objects,
referred to above and emerging from the following detailed description.

[0017] According to a preferred embodiment of the present invention, this
novelty is characterized in that one layer of said formulation provides
controlled release, whereas the other layer provides immediate release.

[0018] According to a preferred embodiment of the present invention, this
formulation comprises one or more excipients.

[0019] According to an embodiment of the present invention, this
formulation comprises at least one intermediate layer.

[0020] According to a preferred embodiment of the present invention, the
trimetazidine is trimetazidine dihydrochloride.

[0021] According to a preferred embodiment of the present invention, the
amount of trimetazidine dihydrochloride in the immediate-release layer is
not more than 25% and is preferably 10% by weight of the total amount of
trimetazidine dihydrochloride present in the tablet.

[0022] According to a preferred embodiment of the present invention, the
controlled-release providing agent contains one or a mixture of
polymethacrylate, glyceryl behenate, polyvinylpyrrolidone (povidone),
cross-linked polyvinylpyrrolidone, hydroxypropyl methyl cellulose (HPMC),
hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methyl
cellulose (MC), ethyl cellulose (EC) and other cellulose derivatives,
polyethylene oxide and gelatin; but this controlled-release agent is
preferably polyethylene oxide. The controlled-release agent is used in
the outer granule phase.

[0023] According to a preferred embodiment of the present invention, the
ratio of trimetazidine dihydrochloride in said controlled-release layer
to polyethylene oxide is between 0.05 to 10, preferably 0.1 to 5, and
more preferably 0.2 to 0.8.

[0024] According to a preferred embodiment of the present invention, the
excipients comprise at least one or a mixture of binders, diluents,
disintegrants, glidants, and lubricants.

[0025] According to a preferred embodiment of the present invention, the
binder comprises at least one or a mixture of cellulose derivatives, such
as polyvinylpyrrolidone (povidone), hydroxypropyl methyl cellulose,
hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl
cellulose; and gelatin; but is preferably polyvinylpyrrolidone.

[0026] According to a preferred embodiment of the present invention, the
diluents comprise at least one or a mixture of lactose, starch, mannitol,
calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate
anhydrate, calcium phosphate trihydrate, silicium dioxide and glucose;
but is preferably selected from calcium hydrogen phosphate dihydrate and
dicalcium hydrogen phosphate anhydrate.

[0027] According to a preferred embodiment of the present invention, the
glidants comprise at least one or a mixture of colloidal silicone
dioxide, talc, aluminum silicate, and magnesium silicate; but is
preferably colloidal silicone dioxide.

[0028] According to a preferred embodiment of the present invention, the
formulation comprises magnesium stearate as a lubricant.

[0029] Another preferred embodiment according to the present invention
consists of:

[0041] A further preferred embodiment according to the present invention
provides a method for preparing a pharmaceutical formulation, this method
comprising the steps of: [0042] a) sieving and then mixing
trimetazidine dihydrochloride, polyvinylpyrrolidone and calcium hydrogen
phosphate dihydrate in a high-shear mixer; [0043] b) granulating the
mixture from above with sufficient amount of water; [0044] c) sieving the
wet granules formed, then drying the same and sieving back the dried
granules; [0045] d) adding polyethylene oxide and colloidal silicone
dioxide into the granules obtained and mixing the latter; [0046] e)
sieving magnesium stearate and mixing it into the resultant mixture to
obtain the controlled-release phase; [0047] f) sieving and mixing
together trimetazidine dihydrochloride, dicalcium hydrogen phosphate
anhydrate, colloidal silicone dioxide and red iron oxide; [0048] g)
sieving magnesium stearate and mixing it into the resultant mixture to
obtain the immediate-release phase; and [0049] h) compacting the
controlled-release phase and immediate-release phase to provide a bilayer
tablet.

[0051] Trimetazidine dihydrochloride, polyvinylpyrrolidone and calcium
hydrogen phosphate dihydrate are sieved and mixed in a high-shear mixer.
The resulting mixture is then granulated with an adequate amount of
water. Wet granules formed are sieved, then dried and the dried granules
are sieved back. Polyethylene oxide and colloidal silicone dioxide are
added into and mixed together with the granules obtained. Polyethylene
oxide providing controlled release is used in the outer granule phase.
When polyethylene oxide is included into wet granules, it leads to
problems of sticking over the machinery and equipment surfaces. Thus,
polyethylene oxide is used in the outer phase to prevent this problem so
that a substantial potential problem is avoided. Magnesium stearate is
added into and mixed with this mixture to produce the controlled-release
phase.

Producing the Immediate-Release Phase

[0052] Trimetazidine dihydrochloride, dicalcium hydrogen phosphate
anhydrate, colloidal silicone dioxide and red iron oxide are mixed in a
separate kettle. To this obtained mixture, sieved magnesium stearate is
added to directly give the immediate-release phase. The
controlled-release phase and the immediate-release phase are compacted to
provide a bilayer tablet.

[0053] The following table provides comparative data of dissolution
profiles of Vastarel MR and the formulation coded 01C10 developed by the
inventors.

[0055] Generally, when some controlled release agents are included into
wet granules, it leads to problems of sticking over the machinery and
equipment surfaces. Controlled release agents are used in the outer phase
so that these agents prevent problems of sticking over the machinery and
equipment. According to a preferred embodiment of the present invention,
the controlled-release providing agent comprises at least one or a
mixture of polymethacrylate, glyceryl behenate, polyvinylpyrrolidone
(povidone), cross-linked polyvinylpyrrolidone, hydroxypropyl methyl
cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose
(CMC), methyl cellulose (MC), ethyl cellulose (EC) and other cellulose
derivatives, polyethylene oxide and gelatin; said controlled-release
agent is preferably selected from glyceryl behenate, hydroxypropyl methyl
cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose
(CMC), methyl cellulose (MC), ethyl cellulose (EC) and other cellulose
derivatives, polyethylene oxide and gelatin. According to one version,
the controlled-release agent is preferably polyethylene oxide.

[0056] These studies conducted at 0.1N HCl show that the 01C01 coded
product according to the present invention dissolves more, particularly
during the first 3 hours. Thus, the time for the treatment onset is
shortened.

[0057] This formulation is embodied for 35 and 70 mg trimetazidine
tablets. 35 mg and 70 mg tablets are developed to provide drug activity
up to 24 hours.

[0058] This invention has surprisingly provided a bilayer tablet
formulation containing trimetazidine dihydrochloride, which does not
stick to machinery during production and shows desired release profiles.
The amounts of immediate-release and controlled-release phases in said
bilayer tablet are such determined that 35 and 70 mg formulations are
obtained of convenient and desired quality, which provide drug release up
to 24 hours. The amount of trimetazidine dihydrochloride in said
immediate-release layer is not more than 25% and is preferably 10% by
weight of the total amount of trimetazidine dihydrochloride present in
the tablet.

[0059] The formulation developed is used in treating angina pectoris,
chorioretinal vascular disorders, tinnitus, vertigo, and meniere's
syndrome.

[0060] Although the tablet obtained is bilayered, it is alternatively
possible to design said tablet with more layers as well. It is possible
to place one or more intermediate layers between the layers that contain
the active agent in order to combine the layers, such intermediate layers
possibly including an active agent or not including an active agent, and
providing immediate release or controlled release. Whilst both layers
including the active agent may provide controlled release or immediate
release, at least one thereof may provide immediate release while the
others provide controlled, prolonged, and retarded release.

[0061] It is additionally possible to use the following additional
auxiliaries in the formulation.

[0067] Suitable coating agents include, but are not restricted to
hydroxypropyl methyl cellulose, polyethylene glycol,
polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer
(PVP-VA), polyvinyl alcohol and other polymers, and all kinds of
Opadry®, as well as pigments, dyes, titanium dioxide and iron oxide
and talc.

[0068] The protection scope of the present invention is set forth in the
following claims and cannot be restricted to the illustrative disclosures
given above, under the detailed description. Any alternative embodiments
to be produced by persons skilled in the art according to the basic
principles, which are under the protection scope as set forth in the
claims, shall be an infringement of the present invention.